Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis within the plane of the epithelium, the latter referred to as Planar Cell Polarity (or PCP). Both, cell polarity and ordered cellular patterning during organogenesis depend on PCP mechanisms. Typical PCP examples include in Drosophila, and insects in general, all cuticular structures and the compound eyes. Similarly, in mammals aspects of PCP are evident in mammalian skin, the inner ear epithelium with its sensory cilia, or the respiratory system and almost all other internal organs. Moreover, convergent extension processes during gastrulation and neural tube patterning and closure requires PCP signaling. PCP establishment in Drosophila serves as a paradigm to study this type of polarity in development and disease. PCP is coordinated by long-range signals from Wnts, resulting in asymmetric localization of the Frizzled (Fz) receptor (with Wnt family members as their ligands) and its associated signaling cascade. The core Fz/PCP factors are required to interpret the polarity within the cell and relay it to neighboring cells. All members of the core Fz/PCP group are conserved throughout evolution and regulate all PCP aspects of coordinated cellular polarization. Wnt-Fz/PCP signaling is distinct from the canonical Wnt-Fz/?-catenin pathway (and correct regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical for development and disease). In PCP- signaling Fz acts both, as the receptor for Wnts and a ligand for its intercellular binding partner Vang/Stbm (Vangl1/2 in mammals). The cellular mechanism(s) acting downstream of Vang/Vangl upon Fz binding are unknown. The scope and focus of this application is to investigate the mechanistic and regulatory interactions of Vang/Vangl as a result of these intercellular interactions, and their integration within the core PCP interaction framework. Based on exciting preliminary data, we propose as Specific Aims to (1) establish the physiological significance of Fz-induced Vang phosphorylation and associated kinase function, (2) to functionally dissect the molecular interactions of Vang/Vangl and its cytoplasmic effectors, a process that will also be aided by including patient data with Vangl associated neural tube closure defects, and (3) define a novel molecular and cellular mechanism as a response downstream of Vang to its intercellular Fz interaction. A combination of in vivo studies in Drosophila, cell culture analyses in mouse skin cells and Drosophila cells, and biochemical experiments will be performed to achieve these goals. Post-translational modification events will be given special attention. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities, ranging from deafness to spina bifida/neural tube closure defects, and cancer, or poly-cystic kidney disease and ciliopathies in general. Information acquired here will both advance our understanding of cellular polarization, and provide medical relevance in many disease contexts.